Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in adults and is characterized in many cases by a progressive clinical course in which conventional treatments, such as chemotherapy, may palliate symptoms but unfortunately do not provide an established cure. Therefore, there is an urgent need for new and more effective therapeutic strategies that involve different mechanisms of action. [unreadable] [unreadable] Several features of this disease suggest that immune-based strategies may have therapeutic potential. Therefore, our group has developed strategies that enhance the ability of CLL cells to interact with T cells and promote effective anti-leukemia responses through a mechanism of Enhanced Antigen Presentation. One is the use of in vitro transduction of CLL cells using adenovirus encoding CD154 (Ad-CD154). This approach has proven to be effective in a recently completed clinical trial in which patients treated with this modality had increased T cell counts, decreased lymph node size and fewer circulating leukemia cells. A second immune-based strategy in CLL is the use of DNA oligodeoxynucleotides (ODN), which activates CLL cells, enhances their function as antigen presenting cells and most importantly improves infectibility and transgene expression of Ad-CD 154. [unreadable] [unreadable] The proposal presented here will investigate the mechanism of ODN mediated activation in CLL cells and the potential synergistic effect in combination with Ad-CD154. Also, we will use this model of Enhanced Antigen Presentation to expand and clone reactive/cytolytic anti-leukemia T cells from CLL patients. Using Positional Scanning Synthetic Combinatorial Peptide Libraries, we propose to characterize specific peptide ligands to those reactive/cytolytic T cells. [unreadable] [unreadable]